People who work the night shift or work irregular hours and eat at irregular hours are more prone to weight gain and diabetes, likely due to eating habits that don’t align with natural daylight and usual meal times. But is it possible to avoid the negative effects of eating at these “unusual” times, even though it’s not biologically preferable? A new study from the Perelman School of Medicine at the University of Pennsylvania says “yes,” shedding light on how the body knows when to eat. Published in Science, the study explains how researchers discovered a link between the liver’s internal clock and the feeding centers in the brain.

Influencing the Communication Pathway Between the Liver and the Brain is a Promising Approach to Weight Management in Individuals With a Disrupted Circadian Rhythm

The team’s research showed that the liver sends signals to the brain via the vagus nerve that tell the brain whether food is being eaten at a time that matches the body’s circadian rhythm. These signals can be disrupted by unusual working hours. The brain then overcompensates, leading to overeating at the wrong times. “Both mice and humans typically eat at times when they are awake and alert, and this cycle provides feedback from the liver to the central clock in the brain, which ensures that the system runs smoothly,” said the study’s senior author, Mitchell Lazar, MD, PhD, director of Penn Medicine’s Institute for Diabetes, Obesity and Metabolism and Ware Professor of Diabetes and Metabolic Diseases. This feedback occurs via a neural connection from the liver to the brain.

Specifically, the researchers focused on genes called REV-ERBs in the liver cells of mice. REV-ERBs are important proteins that regulate the body’s circadian rhythm. The body’s circadian rhythm is an internal 24-hour cycle that regulates various activities, including sleep-wake cycles, hormone secretion and eating habits. When these REV-ERB genes were turned off in mice, giving the liver a faulty clock, eating habits changed dramatically, with more food being consumed at less active times. The effects were reversible. Disrupting the neural connection in obese mice restored normal eating habits and reduced food intake. According to the researchers, this suggests that targeted manipulation of this communication pathway between the liver and the brain could be a promising approach to weight management in individuals with a disrupted circadian rhythm.

The research team hypothesizes that targeting certain parts of the vagus nerve could help people who work night shifts or suffer from jet lag by combating the overeating caused by disrupted body clocks. These findings pave the way for future therapies that can target specific neural pathways to help people struggling with metabolic disorders caused by irregular mealtimes. Future research should focus on what kind of chemical signals the liver sends to the vagus nerve to understand how the liver affects the brain and body through this communication.

More than 3,000 Epigenetic Switches Control Daily Liver Cycles

But how exactly is activity in the liver controlled? Scientists at the Salk Institute have identified the specific genetic switches that synchronize liver activity with the circadian cycle. Their findings provide further insights into the mechanisms behind health-threatening conditions such as high blood sugar and high cholesterol levels. “We know that genes in the liver are switched on and off at different times of the day and are involved in metabolizing substances such as fat and cholesterol,” said Satchidananda Panda, co-corresponding author of the article and associate professor in the Salk’s Laboratory for Regulatory Biology. To understand what turns these genes on or off, the researchers needed to find the switches.

To their surprise, they discovered that among these switches was chromatin, the protein complex that tightly packages DNA in the cell nucleus. Although chromatin is well known for its role in controlling genes, it was not previously suspected to be affected by circadian cycles. In the last decade, scientists have begun to learn more about the relationship between circadian cycles and metabolism. Circadian cycles affect almost all living organisms, including plants, bacteria, insects and humans. In humans and other vertebrates, a brain structure called the suprachiasmatic nucleus controls circadian responses. But there are also clocks throughout the body, including our internal organs, which tell certain genes when to make the workhorse proteins that enable basic functions in our body, such as producing glucose for energy.

In the liver, genes that control fat and cholesterol metabolism are turned on and off in sync with these clocks. However, genes don’t just turn themselves on and off. Their activity is regulated by the “epigenome,” a set of molecules that signal genes how many proteins they should make and, most importantly from a circadian perspective, when to make them. In the liver of mice, they discovered more than 3,000 epigenomic elements that regulate the circadian cycles of 14,492 genes. When comparing the mouse genome to the human genome, they found many of the same genes. This has brought researchers one step closer to understanding the mechanism of gene regulation.